By: Nathan York
Wiskott–Aldrich Syndrome (WAS) is a primary genetic disorder that results in a combined immunodeficiency syndrome in children. It is a rare disease (four cases per million live male births), with a characteristic clinical presentation, making it a good case for the USMLE. It is characterized by the triad of eczema, thrombocytopenia and recurrent fungal, bacterial and viral infections. This disease is caused by a mutation in the gene that encodes Wiskott–Aldrich syndrome protein, or WASP, which is located on the X chromosome. This gene is expressed in all hematopoietic stem cells and appears to be involved in cytoskeletal functions. Dysfunction of this protein results in progressive decrease in the number and function of T cells. This lack of functional T cells also causes an inappropriate B cell response, due to the lack of necessary cytokines for activation and class-switching. The result is an ineffectual response to foreign antigens. Interestingly, these patients develop allergic reactions and eczema as a result of elevated IgE levels in the blood.
As an X-linked disorder, this disease will only appear in males. It can manifest itself in several different ways, because of its effect on hematopoietic development. Within the first few months of life, gastrointestinal bleeding can be detected due to thrombocytopenia, and is often the first sign of the disease. This bleeding tends to become less severe as the child matures. Other early signs include the appearance of purpura and excess bleeding from circumcision. As maternal IgG decreases in the infant’s blood (around six months of age), recurrent infections begin to occur, with particularly poor protection from polysaccharide and protein antigens leading to pneumonia and meningitis. Recurrent infections of any kind should automatically suggest some sort of immune deficiency in the differential diagnosis. As the child approaches one year of age, eczema and food allergies develop (See Figure 1). Remember, for the USMLE, WAS presents as the classic triad of immunodeficiency (recurrent infections), eczema and thrombocytopenia.
Diagnosis, Treatment and Prognosis
Diagnosis of WAS can be made by the following criteria:
-Demonstration of thrombocytopenia (platelet count of 5,000-10,000/uL)
-Presence of small platelets by histology (see Figure 2)
-characteristic of WAS
-Progressive decline in T cell number
-Immunoglobulin profile (decreased IgM, increased IgA and IgE, normal IgG)
Treatment of WAS includes the following:
-Bone marrow transplant (reconstitution of T and B cells)
-Splenectomy to manage thrombocytopenia
-Prompt treatment with antimicrobial agents upon infection
Prognosis of patients with WAS is bleak, if not detected. Without treatment, the average life span is approximately three years. With aggressive treatment, the average life span increases greatly, with some living more than 30 years. However, long-term survival increases risk of malignancies, especially within the lymphoid compartment.
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2. Gupta, K., Pulliam, L. Concepts in Microbiology, Immunology and Infectious Disease. 1997. Parthenon Publishing Group. New York, NY.